The Accuracy of Neutron Star Radius Measurement with the Next Generation of Terrestrial Gravitational-Wave Observatories

In this paper, we explore the prospect for improving the measurement accuracy of masses and radii of neutron stars. We consider imminent and long-term upgrades of the Laser Interferometer Gravitational-Wave Observatory (LIGO) and Virgo, as well as next-generation observatories -- the Cosmic Explorer and Einstein Telescope. We find that neutron star radius with single events will be constrained to within roughly 500m with the current generation of detectors and their upgrades. This will improve to 200m, 100m and 50m with a network of observatories that contain one, two or three next-generation observatories, respectively. Combining events in bins of 0.05 solar masses we find that for stiffer (softer) equations-of-state like ALF2 (APR4), a network of three XG observatories will determine the radius to within 30m (100m) over the entire mass range of neutron stars from 1 to 2.0 solar masses (2.2 solar masses), allowed by the respective equations-of-state. Neutron star masses will be measured to within 0.5 percent with three XG observatories irrespective of the actual equation-of-state. Measurement accuracies will be a factor of 4 or 2 worse if the network contains only one or two XG observatories, respectively, and a factor of 10 worse in the case of networks consisting of Advanced LIGO, Virgo KAGRA and their upgrades. Tens to hundreds of high-fidelity events detected by future observatories will allow us to accurately measure the mass-radius curve and hence determine the dense matter equation-of-state to exquisite precision

A facility design for repackaging ORNL CH-TRU legacy waste in Building 3525

For the last 25 years, the Oak Ridge National Laboratory (ORNL) has conducted operations which have generated solid, contact-handled transuranic (CH-TRU) waste. At present the CH-TRU waste inventory at ORNL is about 3400 55-gal drums retrievably stored in RCRA-permitted, aboveground facilities. Of the 3400 drums, approximately 2600 drums will need to be repackaged. The current US Department of Energy (DOE) strategy for disposal of these drums is to transport them to the Waste Isolation Pilot Plant (WIPP) in New Mexico which only accepts TRU waste that meets a very specific set of criteria documented in the WIPP-WAC (waste acceptance criteria). This report describes activities that were performed from January 1994 to May 1995 associated with the design and preparation of an existing facility for repackaging and certifying some or all of the CH-TRU drums at ORNL to meet the WIPP-WAC. For this study, the Irradiated Fuel Examination Laboratory (IFEL) in Building 3525 was selected as the reference facility for modification. These design activities were terminated in May 1995 as more attractive options for CH-TRU waste repackaging were considered to be available. As a result, this document serves as a final report of those design activities

A Horizon Study for Cosmic Explorer: Science, Observatories, and Community

Gravitational-wave astronomy has revolutionized humanity's view of the universe. Investment in the field has rewarded the scientific community with the first direct detection of a binary black hole merger and the multimessenger observation of a neutron-star merger. Each of these was a watershed moment in astronomy, made possible because gravitational waves reveal the cosmos in a way that no other probe can. Since the first detection of gravitational waves in 2015, the National Science Foundation's LIGO and its partner observatory, the European Union's Virgo, have detected over fifty binary black hole mergers and a second neutron star merger -- a rate of discovery that has amazed even the most optimistic scientists.This Horizon Study describes a next-generation ground-based gravitational-wave observatory: Cosmic Explorer. With ten times the sensitivity of Advanced LIGO, Cosmic Explorer will push the gravitational-wave astronomy towards the edge of the observable universe ($z \sim 100$). This Horizon Study presents the science objective for Cosmic Explorer, and describes and evaluates its design concepts for. Cosmic Explorer will continue the United States' leadership in gravitational-wave astronomy in the international effort to build a "Third-Generation" (3G) observatory network that will make discoveries transformative across astronomy, physics, and cosmology

Outcome Measures for Disease-Modifying Trials in Parkinson\u27s Disease: Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative

\ua9 2023-The authors. Published by IOS Press.Background: Multi-Arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson\u27s disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. Objective: To provide an up-To-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. Methods: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives\u27 input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. Results: An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. Conclusion: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges

Embedding Patient Input in Outcome Measures for Long-Term Disease-Modifying Parkinson Disease Trials

BACKGROUND: Clinical trials of disease-modifying therapies in PD require valid and responsive primary outcome measures that are relevant to patients. OBJECTIVES: The objective is to select a patient-centered primary outcome measure for disease-modification trials over three or more years. METHODS: Experts in Parkinson's disease (PD), statistics, and health economics and patient and public involvement and engagement (PPIE) representatives reviewed and discussed potential outcome measures. A larger PPIE group provided input on their key considerations for such an endpoint. Feasibility, clinimetric properties, and relevance to patients were assessed and synthesized. RESULTS: Although initial considerations favored the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in Off, feasibility, PPIE input, and clinimetric properties supported the MDS-UPDRS Part II. However, PPIE input also highlighted the importance of nonmotor symptoms, especially in the longer term, leading to the selection of the MDS-UPDRS Parts I + II sum score. CONCLUSIONS: The MDS-UPDRS Parts I + II sum score was chosen as the primary outcome for large 3-year disease-modification trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Metric Assisted Stochastic Sampling (MASS) search for gravitational waves from binary black hole mergers

We present a novel gravitational wave detection algorithm that conducts amatched filter search stochastically across the compact binary parameter spacerather than relying on a fixed bank of template waveforms. This technique iscompetitive with standard template-bank-driven pipelines in both computationalcost and sensitivity. However, the complexity of the analysis is simplerallowing for easy configuration and horizontal scaling across heterogeneousgrids of computers. To demonstrate the method we analyze approximately onemonth of public LIGO data from July 27 00:00 2017 UTC - Aug 25 22:00 2017 UTCand recover eight known confident gravitational wave candidates. We also injectsimulated binary black hole (BBH) signals to demonstrate the sensitivity.<br

Outcome Measures for Disease-Modifying Trials in Parkinson's Disease:Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative

BACKGROUND: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach.OBJECTIVE: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials.METHODS: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory.RESULTS: An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages.CONCLUSION: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges.</p

Outcome Measures for Disease-Modifying Trials in Parkinson's Disease: Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative

BACKGROUND: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. OBJECTIVE: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. METHODS: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. RESULTS: An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. CONCLUSION: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges

Structure-Function Relationship of Cytoplasmic and Nuclear IκB Proteins: An In Silico Analysis

Cytoplasmic IκB proteins are primary regulators that interact with NF-κB subunits in the cytoplasm of unstimulated cells. Upon stimulation, these IκB proteins are rapidly degraded, thus allowing NF-κB to translocate into the nucleus and activate the transcription of genes encoding various immune mediators. Subsequent to translocation, nuclear IκB proteins play an important role in the regulation of NF-κB transcriptional activity by acting either as activators or inhibitors. To date, molecular basis for the binding of IκBα, IκBβ and IκBζ along with their partners is known; however, the activation and inhibition mechanism of the remaining IκB (IκBNS, IκBε and Bcl-3) proteins remains elusive. Moreover, even though IκB proteins are structurally similar, it is difficult to determine the exact specificities of IκB proteins towards their respective binding partners. The three-dimensional structures of IκBNS, IκBζ and IκBε were modeled. Subsequently, we used an explicit solvent method to perform detailed molecular dynamic simulations of these proteins along with their known crystal structures (IκBα, IκBβ and Bcl-3) in order to investigate the flexibility of the ankyrin repeat domains (ARDs). Furthermore, the refined models of IκBNS, IκBε and Bcl-3 were used for multiple protein-protein docking studies for the identification of IκBNS-p50/p50, IκBε-p50/p65 and Bcl-3-p50/p50 complexes in order to study the structural basis of their activation and inhibition. The docking experiments revealed that IκBε masked the nuclear localization signal (NLS) of the p50/p65 subunits, thereby preventing its translocation into the nucleus. For the Bcl-3- and IκBNS-p50/p50 complexes, the results show that Bcl-3 mediated transcription through its transactivation domain (TAD) while IκBNS inhibited transcription due to its lack of a TAD, which is consistent with biochemical studies. Additionally, the numbers of identified flexible residues were equal in number among all IκB proteins, although they were not conserved. This could be the primary reason for their binding partner specificities